CLINICAL PHARMACOLOGY

Mechanism Of Action

Pharmacodynamics

ECG Evaluation

The effect of APTIVUS/ritonavir on the QTcF interval was
measured in a study in which 81 healthy subjects received the following
treatments twice daily for 2.5 days: APTIVUS/ritonavir (500/200 mg),
APTIVUS/ritonavir at a supra-therapeutic dose (750/200 mg), and
placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the
maximum mean QTcF change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the
500/200 mg dose and 8.3 ms (1-sided 95% Upper CI: 10.9 ms) for the
supra-therapeutic 750/200 mg dose.

Antiviral Activity in vivo

The median Inhibitory Quotient (IQ) determined from 264
treatment-experienced adult patients was about 80 (inter-quartile range:
31-226), from the controlled clinical trials 1182.12 and 1182.48. The IQ is
defined as the tipranavir trough concentration divided by the viral EC50 value,
corrected for protein binding. There was a relationship between the proportion
of patients with a ≥ 1 log10 reduction of viral load from baseline at week
48 and their IQ value. Among the 198 patients receiving APTIVUS/ritonavir with
no new enfuvirtide use (e.g., new enfuvirtide, defined as initiation of
enfuvirtide for the first time), the response rate was 23% in those with an IQ
value < 80 and 59% in those with an IQ value ≥ 80. Among the 66 patients
receiving APTIVUS/ritonavir with new enfuvirtide, the response rates in
patients with an IQ value < 80 versus those with an IQ value ≥ 80 were
55% and 71%, respectively. These IQ groups are derived from a select population
and are not meant to represent clinical breakpoints.

Pharmacokinetics

In order to achieve effective tipranavir plasma
concentrations and a twice-daily dosing regimen, co-administration of APTIVUS
with ritonavir is essential [see DOSAGE AND ADMINISTRATION]. Ritonavir
inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pump
and possibly intestinal CYP 3A. In a dose-ranging evaluation in 113 HIV-1
negative male and female volunteers, there was a 29-fold increase in the
geometric mean morning steady-state trough plasma concentrations of tipranavir
following APTIVUS co-administered with low-dose ritonavir (500/200 mg twice
daily) compared to APTIVUS 500 mg twice daily without ritonavir. In adults the
mean systemic ritonavir concentration when 200 mg of ritonavir was given with
500 mg of APTIVUS was similar to the concentrations observed when 100 mg was
given with the other protease inhibitors.

Absorption and Bioavailability

Absorption of tipranavir in
humans is limited, although no absolute quantification of absorption is
available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears
to be a potent P-gp inducer as well. In vivo data suggest that tipranavir/ritonavir,
at the dose of 500/200 mg, is a P-gp inhibitor after the first dose and
induction of P-gp occurs over time. Tipranavir trough concentrations at
steady-state are about 70% lower than those on Day 1, presumably due to
intestinal P-gp induction. Steady state is attained in most subjects after 7-10
days of dosing.

Effects of Food on Oral Absorption

For APTIVUS capsules or oral solution
co-administered with ritonavir capsules at steady-state, no clinically
significant changes in tipranavir Cmax, Cp12h, and AUC were observed under fed
conditions (500-682 Kcal, 23-25% calories from fat) compared to fasted
conditions [see DOSAGE AND ADMINISTRATION]. The effect of food on
tipranavir exposure when APTIVUS capsules or oral solution is co-administered
with ritonavir tablets has not been evaluated [see DOSAGE AND ADMINISTRATION].
For information on the effect of food on the bioavailability of ritonavir
tablets, please refer to the ritonavir tablet prescribing information.

Distribution

Tipranavir is extensively bound
to plasma proteins ( > 99.9%). It binds to both human serum albumin and
α-1-acid glycoprotein. The mean fraction of tipranavir (dosed without
ritonavir) unbound in plasma was similar in clinical samples from healthy
volunteers and HIV-1 positive patients. Total plasma tipranavir concentrations
for these samples ranged from 9 to 82 μM. The unbound fraction of tipranavir
appeared to be independent of total drug concentration over this concentration
range.

No studies have been conducted to determine the
distribution of tipranavir into human cerebrospinal fluid or semen.

Metabolism

The oral clearance of tipranavir decreased after the
addition of ritonavir, which may represent diminished first-pass clearance of
the drug at the gastrointestinal tract as well as the liver.

The metabolism of tipranavir in the presence of 200 mg
ritonavir is minimal. Administration of 14C-tipranavir to subjects
that received APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstrated
that unchanged tipranavir accounted for 98.4% or greater of the total plasma
radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few
metabolites were found in plasma, and all were at trace levels (0.2% or less of
the plasma radioactivity). In feces, unchanged tipranavir represented the
majority of fecal radioactivity (79.9% of fecal radioactivity). The most
abundant fecal metabolite, at 4.9% of fecal radioactivity (3.2% of dose), was a
hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in
trace amounts (0.5% of urine radioactivity). The most abundant urinary
metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide
conjugate of tipranavir.

Elimination

Administration of 14C-tipranavir to subjects
(n=8) that received APTIVUS/ritonavir 500/200 mg dosed to steady-state
demonstrated that most radioactivity (median 82.3%) was excreted in feces,
while only a median of 4.4% of the radioactive dose administered was recovered
in urine. In addition, most radioactivity (56%) was excreted between 24 and 96
hours after dosing. The effective mean elimination half-life of
tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infected adult
patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady
state following a dose of 500/200 mg twice daily with a light meal.

Special Populations

Renal Impairment

APTIVUS pharmacokinetics have not been studied in
patients with renal dysfunction. However, since the renal clearance of
tipranavir is negligible, a decrease in total body clearance is not expected in
patients with renal insufficiency.

Hepatic Impairment

In a study comparing 9 HIV-1 negative patients with mild
(Child-Pugh Class A) hepatic impairment to 9 HIV-1 negative controls, the
single and multiple dose plasma concentrations of tipranavir and ritonavir were
increased in patients with hepatic impairment, but were within the range
observed in clinical trials. No dosing adjustment is required in patients with
mild hepatic impairment.

The influence of moderate hepatic impairment (Child-Pugh
Class B) or severe hepatic impairment (Child-Pugh Class C) on the multiple-dose
pharmacokinetics of tipranavir administered with ritonavir has not been
evaluated [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS
AND PRECAUTIONS].

Gender

Evaluation of steady-state plasma tipranavir trough
concentrations at 10-14 h after dosing from the controlled clinical trials
1182.12 and 1182.48 demonstrated that females generally had higher tipranavir
concentrations than males. After 4 weeks of APTIVUS/ritonavir 500/200 mg BID,
the median plasma trough concentration of tipranavir was 43.9 μM for
females and 31.1 μM for males. The difference in concentrations does not
warrant a dose adjustment.

Race

Evaluation of steady-state plasma tipranavir trough
concentrations at 10-14 h after dosing from the controlled clinical trials
1182.12 and 1182.48 demonstrated that white males generally had more
variability in tipranavir concentrations than black males, but the median
concentration and the range making up the majority of the data are comparable
between the races.

Geriatric Patients

Evaluation of steady-state plasma tipranavir trough concentrations
at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48
demonstrated that there was no change in median trough tipranavir
concentrations as age increased for either gender through 65 years of age.
There were an insufficient number of women greater than age 65 years in the two
trials to evaluate the elderly.

Pediatric Patients

Among pediatric patients in clinical trial 1182.14,
steady-state plasma tipranavir trough concentrations were obtained 10 to 14
hours following study drug administration. Pharmacokinetic parameters by age
group are presented in Table 6.

Drug Interactions

Drug interaction studies were
performed with APTIVUS capsules co-administered with ritonavir, and other drugs
likely to be co-administered and some drugs commonly used as probes for
pharmacokinetic interactions. The effects of co-administration of APTIVUS with
200 mg ritonavir on the AUC, Cmax, and Cmin of tipranavir or the
co-administered drug, are summarized in Tables 7 and 8, respectively. For
information regarding clinical recommendations see DRUG INTERACTIONS.

Microbiology

Mechanism of Action

Tipranavir (TPV) is an HIV-1
protease inhibitor that inhibits the virus-specific processing of the viral Gag
and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of
mature virions.

Antiviral Activity

Tipranavir inhibits the replication
of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell
infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07
μM (18-42 ng/mL). Tipranavir demonstrates antiviral activity in cell
culture against a broad panel of HIV-1 group M non-clade B isolates (A, C, D,
F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced
susceptibility in cell culture to tipranavir with EC50 values ranging from
0.164 -1 μM and 0.233-0.522 μM, respectively. When used with other
antiretroviral agents in cell culture, the combination of tipranavir was
additive to antagonistic with other protease inhibitors (amprenavir,
atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and
generally additive with the NNRTIs (delavirdine, efavirenz, and nevirapine) and
the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine,
tenofovir, and zidovudine). Tipranavir was synergistic with the HIV-1 fusion
inhibitor enfuvirtide. There was no antagonism of the cell culture combinations
of tipranavir with either adefovir or ribavirin, used in the treatment of viral
hepatitis.

Resistance

In cell culture

HIV-1 isolates with a decreased
susceptibility to tipranavir have been selected in cell culture and obtained
from patients treated with APTIVUS/ritonavir (TPV/ritonavir). After 9 months of
culture in TPV-containing media, HIV-1 isolates with 87-fold reduced
susceptibility to tipranavir were selected in cell culture; these contained 10
protease substitutions that developed in the following order: L33F, I84V, K45I,
I13V, V32I, V82L, M36I, A71V, L10F, and I54V/T. Changes in the Gag polyprotein
CA/P2 cleavage site were also observed following drug selection. Experiments
with site-directed mutants of HIV-1 showed that the presence of 6 substitutions
in the protease coding sequence (I13V, V32I, L33F, K45I, V82L, I84V) conferred
> 10-fold reduced susceptibility to tipranavir.

Clinical Studies of
Treatment-Experienced Patients

In controlled clinical trials
1182.12 and 1182.48, multiple protease inhibitor-resistant HIV-1 isolates from
59 treatment-experienced adult patients who received APTIVUS/ritonavir and
experienced virologic rebound developed amino acid substitutions that were
associated with resistance to tipranavir. The most common amino acid
substitutions that developed on 500/200 mg APTIVUS/ritonavir in greater than
20% of APTIVUS/ritonavir virologic failure isolates were L33V/I/F, V82T, and
I84V. Other substitutions that developed in 10 to 20% of APTIVUS/ritonavir
virologic failure isolates included L10V/I/S, I13V, E35D/G/N, I47V, I54A/M/V,
K55R, V82L, and L89V/M. Evolution at protease gag polyprotein cleavage sites
was also observed. Among 28 pediatric patients in clinical trial 1182.14 who
experienced virologic failure or non-response, the emergent protease amino acid
codon substitutions were similar to those observed in adult virologic failure
isolates.

In clinical trials 1182.12 and
1182.48 tipranavir resistance was detected at virologic rebound after an
average of 38 weeks of APTIVUS/ritonavir treatment with a median 14-fold
decrease in tipranavir susceptibility. Similarly, reduced tipranavir
susceptibility was associated with emergent mutations in pediatric patient
isolates.

Cross-resistance

Cross-resistance among protease
inhibitors has been observed. Tipranavir had < 4-fold decreased
susceptibility against 90% (94/105) of HIV-1 clinical isolates resistant to
amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or
saquinavir. Tipranavir-resistant viruses which emerged in cell culture from
wild-type HIV-1 had decreased susceptibility to the protease inhibitors
amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but
remained sensitive to saquinavir.

Baseline Genotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus
may aid in determining tipranavir susceptibility before initiation of
APTIVUS/ritonavir therapy. Several analyses were conducted to evaluate the impact
of specific substitutions and combination of substitutions on virologic
outcome. Both the type and number of baseline protease inhibitor substitutions
as well as use of additional active agents (e.g., enfuvirtide) affected
APTIVUS/ritonavir response rates in controlled clinical trials 1182.12 and
1182.48 through Week 48 of treatment.

As-treated analyses were also conducted to assess
virologic outcome by the number of primary protease inhibitor substitutions
present at baseline. Response rates were reduced if five or more protease inhibitor-associated
substitutions were present at baseline and subjects did not receive concomitant
new enfuvirtide with APTIVUS/ritonavir. See Table 9.

aPrimary PI mutations include any amino acid substitution at
positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90bNo new enfuvirtide is defined as recycled or continued use of
enfuvirtide or no use of enfuvirtide cNew enfuvirtide is defined as initiation of enfuvirtide for the
first time

The median change from baseline
in plasma HIV-1 RNA at weeks 2, 4, 8, 16, 24 and 48 was evaluated by the number
of baseline primary protease inhibitor resistance associated substitutions (1-4
or ≥ 5) in subjects who received APTIVUS/ritonavir with or without new
enfuvirtide. The following observations were made:

Approximately 1.5 log10 decrease in HIV-1 RNA at early
time points (Week 2) regardless of the number of baseline primary protease
inhibitor resistance associated substitutions (1-4 or 5+).

Subjects with 5 or more primary protease inhibitor
resistance associated substitutions in their HIV-1 at baseline who received
APTIVUS/ritonavir without new enfuvirtide (n=303) began to lose their antiviral
response after Week 4.

Early HIV-1 RNA decreases (1.5-2 log10) were sustained
through Week 48 in subjects with 5 or more primary protease inhibitor
resistance associated substitutions at baseline who received new enfuvirtide
with APTIVUS/ritonavir (n=74).

Baseline Phenotype and
Virologic Outcome Analyses

APTIVUS/ritonavir response
rates were also assessed by baseline tipranavir phenotype. Relationships
between baseline phenotypic susceptibility to tipranavir, mutations at protease
amino acid codons 33, 82, 84 and 90, tipranavir resistance-associated
mutations, and response to APTIVUS/ritonavir therapy at Week-48 are summarized
in Tables 10 and 11. These baseline phenotype groups are not meant to represent
clinical susceptibility breakpoints for APTIVUS/ritonavir because the data are
based on the select 1182.12 and 1182.48 patient population. The data are
provided to give clinicians information on the likelihood of virologic success
based on pre-treatment susceptibility to APTIVUS/ritonavir in protease
inhibitor-experienced patients.

aChange in tipranavir EC50 value from wild-type reference bConfirmed ≥ 1 log10 decrease at Week 48 cNo new enfuvirtide is defined as recycled or continued use of
enfuvirtide or no use of enfuvirtidedNew enfuvirtide is defined as initiation of enfuvirtide for the
first time

Analyses of pediatric clinical
trial 1182.14 also demonstrated that response to therapy was influenced by the
number of baseline protease inhibitor mutations present.

Animal Toxicology And/Or Pharmacology

In preclinical studies in rats,
tipranavir treatment induced dose-dependent changes in coagulation parameters
(increased prothrombin time, increased activated partial thromboplastin time,
and a decrease in some vitamin K dependent factors). In some rats, these
changes led to bleeding in multiple organs and death. The coadministration of
vitamin E in the form of TPGS (d-alpha-tocopherol polyethylene glycol 1000
succinate) with tipranavir resulted in a significant increase in effects on
coagulation parameters, bleeding events, and death.

In preclinical studies of
tipranavir in dogs, an effect on coagulation parameters was not seen.
Co-administration of tipranavir and vitamin E has not been studied in dogs.
Clinical evaluation of coagulation effects on HIV-1-infected patients
demonstrated no tipranavir plus ritonavir effect and no effect of the vitamin
E-containing oral solution on coagulation parameters [see Effects on
Platelet Aggregation and Coagulation].

Clinical Studies

Adult Patients

The following clinical data is
derived from analyses of 48-week data from ongoing studies measuring effects on
plasma HIV-1 RNA levels and CD4+ cell counts. At present there are no results
from controlled studies evaluating the effect of APTIVUS/ritonavir on clinical
progression of HIV-1.

The two clinical trials 1182.12
and 1182.48 (RESIST 1 and RESIST 2) are ongoing, randomized, controlled,
open-label, multicenter studies in HIV-1 positive, triple antiretroviral class
experienced patients. All patients were required to have previously received at
least two protease inhibitor-based antiretroviral regimens and were failing a
protease inhibitor-based regimen at the time of study entry with baseline HIV-1
RNA at least 1000 copies/mL and any CD4+ cell count. At least one primary
protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T,
84V or 90M had to be present at baseline, with not more than two mutations at
codons 33, 82, 84 or 90.

These studies evaluated
treatment response at 48 weeks in a total of 1483 patients receiving either
APTIVUS co-administered with 200 mg of ritonavir plus OBR versus a control
group receiving a ritonavir-boosted protease inhibitor (lopinavir, amprenavir,
saquinavir or indinavir) plus OBR. Prior to randomization, OBR was individually
defined for each patient based on genotypic resistance testing and patient
history. The investigator had to declare OBR, comparator protease inhibitor,
and use of new enfuvirtide prior to randomization. Randomization was stratified
by choice of comparator protease inhibitor and use of new enfuvirtide.

After Week 8, patients in the
control group who met the protocol defined criteria of initial lack of
virologic response or confirmed virologic failure had the option of
discontinuing treatment and switching to APTIVUS/ritonavir in a separate
roll-over study.

Demographics and baseline
characteristics were balanced between the APTIVUS/ritonavir arm and control
arm. In both studies combined, the 1483 patients had a median age of 43 years
(range 17-80), and were 86.3% male, 75.6% white, 12.9% black, and 0.9% Asian.
The median baseline plasma HIV-1 RNA for both treatment groups was 4.8 (range
2.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 162 (range
1 to 1894) cells/mm³. Overall, 38.4% of patients had a baseline
HIV-1 RNA of > 100,000 copies/mL, 58.6% had a baseline CD4+ cell count
≤ 200 cells/mm³, and 57.8% had experienced an AIDS defining
Class C event at baseline.

Patients had prior exposure to
a median of 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 10.1% of patients had
previously used enfuvirtide. In baseline patient samples (n=454), 97% of the
HIV-1 isolates were resistant to at least one protease inhibitor, 95% of the
isolates were resistant to at least one NRTI, and > 75% of the isolates were
resistant to at least one NNRTI.

The individually pre-selected
protease inhibitor based on genotypic testing and the patient's medical history
was lopinavir in 48.7%, amprenavir in 26.4%, saquinavir in 21.8% and indinavir
in 3.1% of patients. A total of 85.1% were possibly resistant or resistant to
the pre-selected comparator protease inhibitors. Approximately 21% of patients
used enfuvirtide during the study of which 16.6% in the APTIVUS/ritonavir arm
and 13.2% in the comparator/ritonavir arm represented first time use of
enfuvirtide (new enfuvirtide).

Treatment response and efficacy
outcomes of randomized treatment through Week 48 of studies 1182.12 and 1182.48
are shown in Table 12.

*Comparator protease inhibitors
were lopinavir, amprenavir, saquinavir or indinavir and 85.1% of patients were
possibly resistant or resistant to the chosen protease inhibitors. aPatients achieved and maintained a confirmed ≥ 1 log10 HIV-1
RNA drop from baseline through Week 48 without prior evidence of treatment
failure. bPatients did not achieve a 0.5 log10 HIV-1 RNA drop from baseline and
did not have viral load < 100,000 copies/mL by Week 8. cDeath only counted if it was the reason for treatment failure.dIncludes patients who were lost to-follow-up, withdrawn consent,
non-adherent, protocol violations, added/changed background antiretroviral
drugs for reasons other than tolerability or toxicity, or discontinued while
suppressed.

Through 48 weeks of treatment,
the proportion of patients in the APTIVUS/ritonavir arm compared to the
comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 30.3% and
13.6% respectively, and with HIV-1 RNA < 50 copies/mL was 22.7% and 10.2%
respectively. Among all randomized and treated patients, the median change from
baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/mL
in patients receiving APTIVUS/ritonavir versus -0.22 log10 copies/mL in the
comparator PI/ritonavir arm.

Among all randomized and
treated patients, the median change from baseline in CD4+ cell count at the
last measurement up to Week 48 was +23 cells/mm³in patients
receiving APTIVUS/ritonavir (N=740) versus +4 cells/mm³in the
comparator PI/ritonavir (N=727) arm.

Patients in the APTIVUS/ritonavir
arm achieved a significantly better virologic outcome when APTIVUS/ritonavir
was combined with enfuvirtide. Among patients with new enfuvirtide use, the
proportion of patients in the APTIVUS/ritonavir arm compared to the comparator
PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 52.4% and 19.6%
respectively, and with HIV-1 RNA < 50 copies/mL was 37.3% and 14.4%
respectively [see CLINICAL PHARMACOLOGY]. The median change from
baseline in CD4+ cell count at the last measurement up to Week 48 was +89
cells/mm³in patients receiving APTIVUS/ritonavir in combination
with newly introduced enfuvirtide (N=124) and +18 cells/mm³in the
comparator PI/ritonavir (N=96) arm.

Pediatric Patients

The pharmacokinetic profile,
safety and activity of APTIVUS/ritonavir was evaluated in a randomized,
open-label, multicenter study. This study enrolled HIV-1 infected,
treatment-experienced pediatric patients (with the exception of 3
treatment-na´ve patients), with baseline HIV-1 RNA of at least 1500 copies/mL.
The age ranged from 2 through 18 years and patients were stratified by age (2
to < 6 years, 6 to < 12 years and 12 to 18 years). One hundred and ten
(110) patients were randomized to receive one of two APTIVUS/ritonavir dose
regimens: 375 mg/m²/150 mg/m² dose (N=55) or 290 mg/m²/115
mg/m² dose (N=55), plus background therapy of at least two
non-protease inhibitor antiretroviral drugs, optimized using baseline genotypic
resistance testing. All patients initially received APTIVUS oral solution.
Pediatric patients who were 12 years or older and received the maximum dose of
500/200 mg BID could subsequently change to APTIVUS capsules at day 28 [see ADVERSE
REACTIONS, Use In Specific Populations, CLINICAL PHARMACOLOGY,
and Microbiology].

Demographics and baseline characteristics were balanced
between the APTIVUS/ritonavir dose groups. The 110 randomized pediatric
patients had a median age of 11.7 years (range 2 to
18), and were 57.2% male, 68.1% white, 30% black, and 1.8% Asian. The median
baseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log10 copies/mL and median
baseline CD4+ cell count was 379 (range 2 to 2578) cells/mm³.
Overall, 37.4% of patients had a baseline HIV-1 RNA of > 100,000 copies/mL;
28.7% had a baseline CD4+ cell count ≤ 200 cells/mm³, and 48%
had experienced a prior AIDS defining Class C event at baseline. Patients had
prior exposure to a median of 4 NRTIs, 1 NNRTI, and 2 PIs.

Eighty three (75%) completed
the 48 week period while 25% discontinued prematurely. Of the patients who
discontinued prematurely, 9 (8%) discontinued due to virologic failure, and 9
(8%) discontinued due to adverse reactions.

At 48 weeks, 40% of patients
had viral load < 400 copies/mL. The proportion of patients with viral load
< 400 copies/mL tended to be greater (70%) in the youngest group of patients,
who had less baseline viral resistance, compared to the older groups (37% and
31%). The HIV-1 RNA results are presented in Table 13.

Overall, 6 (5%) patients ages 6 to 18 had AIDS defining
illness during the treatment period and all received the 290 mg/m²/115
mg/m² dose.

The guidance for possible dose reduction for patients who
develop intolerance or toxicity and cannot continue with APTIVUS/ritonavir 14
mg/kg/6 mg/kg (or 375 mg/m²/150 mg/m²) is based on the
following: